Bacteriophages and related endolysins for reduction of microorganisms in the human body – a systematic review

Background: In recent years, resistance to antibiotics has become a global threat, and alternatives to antibiotics have become an area of research. The main alternative methods are briefly described in this review. However, the main focus is bacteriophage-related therapy. Bacteriophages are viruses which, due to the production of the enzyme endolysin, are able to kill bacterial host cells. Bacteriophage therapies have a long tradition. Their potential to function as antibiotics lies in their bactericidal activity and specificity in killing bacteria without infecting or affecting eukaryotic cells. Objective: To systematically review the outcomes of bacteriophage therapy in patients with bacterial infections. Methods: The MEDLINE, EMBASE, Web of Science and CENTRAL databases were searched electronically using search terms referring to bacteriophages, endolysins and antimicrobial resistance. After the literature was screened for their titles and abstracts, full-text reviews considering inclusion/exclusion criteria were performed. Data concerning patients with bacterial infections, treatment with either bacteriophages or its enzyme endolysin and their outcomes were extracted and analysed. Results: Thirteen publications were identified that met all inclusion criteria. Data extraction shows that bacteriophages or endolysins have the potential to combat bacterial infections and significantly reduce inflammatory mediators. However, 3 out of 4 randomized controlled trials revealed that there was no significant difference between phage/endolysin treated patients and control group. Significant clinical improvements were seen in cohort and case studies. A few minor side effects were reported. Conclusions: Although there are countries in which bacteriophages are prescribed as an alternative to established antibiotics, this valuable experience has yet to be examined sufficiently in clinical trials conducted to modern standards. Despite improvements in symptoms shown in the reviewed clinical trials, the infection and the bacteria themselves were rarely completely eradicated. Therefore, no definite answer can be given as to effectiveness, and further clinical trials are necessary.


Rationale
3 Describe the rationale for the review in the context of what is already known. 9-17 Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS).

METHODS
Protocol and registration 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number. n.a.
Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale.

18-19
Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.

20
Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated. 52 Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis).

19-20
Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.

20
Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made.

18-19
Risk of bias in individual studies 12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis.
Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g., I 2 ) for each meta-analysis.

Section/topic # Checklist item Reported on page #
Risk of bias across studies 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies).

Study selection 17
Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram.

21; 47
Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations.

Summary of evidence 24
Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers).

31
Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias).

35-36
Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research. 37

Funding 27
Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review.